{"doi":"10.1101/2023.01.11.523010","title":"Anionic Phospholipids Control Mechanisms of GPCR-G Protein Recognition","abstract":"Abstract G protein-coupled receptors (GPCRs) are embedded in phospholipids that strongly influence drug-stimulated signaling. Anionic lipids are particularly important for GPCR signaling complex formation, but a mechanism for this role is not understood. Using NMR spectroscopy, we visualized the impact of anionic lipids on the function-related conformational equilibria of the human A 2A adenosine receptor (A 2A AR) in bilayers containing defined mixtures of zwitterionic and anionic phospholipids. Anionic lipids primed the receptor to form complexes with G proteins through a conformational selection process. Without anionic lipids, signaling complex formation proceeded through a less favorable induced fit mechanism. In computational models, anionic lipids mimicked interactions between a G protein and positively charged residues in A 2A AR at the receptor intracellular surface, stabilizing a pre-activated receptor conformation. Replacing these residues strikingly altered the receptor response to anionic lipids in experiments. High sequence conservation of the same residues among all GPCRs supports a general role for lipid-receptor charge complementarity in signaling.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":395648,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":777104,"name":"Arka Prabha Ray","orcid":"0000-0002-1810-9261","position":1,"is_corresponding":false},{"id":1020142,"name":"Liam Sharp","orcid":"0000-0003-3653-949X","position":2,"is_corresponding":false},{"id":827715,"name":"Beining Jin","orcid":"0000-0002-4347-4797","position":3,"is_corresponding":false},{"id":827714,"name":"Alexander Duong","orcid":"0000-0002-0884-668X","position":4,"is_corresponding":false},{"id":927228,"name":"Niloofar Gopal Pour","orcid":null,"position":5,"is_corresponding":false},{"id":279425,"name":"Samuel Obeng","orcid":"0000-0002-9644-0750","position":6,"is_corresponding":false},{"id":1020666,"name":"Anuradha V. Wijesekara","orcid":null,"position":7,"is_corresponding":false},{"id":275808,"name":"Zhan‐Guo Gao","orcid":"0000-0002-6663-524X","position":8,"is_corresponding":false},{"id":279431,"name":"Christopher R. McCurdy","orcid":"0000-0001-8695-2915","position":9,"is_corresponding":false},{"id":233845,"name":"Kenneth A. Jacobson","orcid":"0000-0001-8104-1493","position":10,"is_corresponding":false},{"id":363454,"name":"Edward Lyman","orcid":"0000-0003-4590-0363","position":11,"is_corresponding":false},{"id":275810,"name":"Matthew T. Eddy","orcid":"0000-0002-3349-6212","position":12,"is_corresponding":false},{"id":827713,"name":"Naveen Thakur","orcid":"0000-0002-2980-0517","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T01:19:22.857556Z","pmid":"36711594","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}